We have hypothesized that the therapeutic mechanism of antidepressant drugs depends on their effects on the circadian system. This hypothesis is being examined by testing the effects of antidepressant and neuroleptic drugs on the state of the circadian pacemaker that controls daily rhythms of motor activity, temperature and EEG sleep. During the past year this project has focused on two major areas. One area of investigation has been on the effects of chronic psychoactive drug treatment on regulation of brain temperature. These experiments indicate that chronic antidepressant drug treatment with clorgyline, fluoxetine or lithium, lowers hypothalamic temperature, particularly during the rest phase of the circadian cycle. In contrast, chronic treatment with the neuroleptic drugs chlorpromazine or haloperidol increase hypothalamic temperature. Further research is required to understand the mechanisms through which these drugs alter hypothalamic temperature. For example, it is possible that antidepressant drugs decrease the set-point of hypothalamic temperature regulation, possibly through their serotonergic properties. These drugs, through multiple effects on circulating hormones and neurotransmitters, could also alter hypothalamic temperature by changing blood flow to the hypothalamus. In depressed patients, elevated body temperature is often observed during rest and pharmacological and non-pharmacological treatments of depression have been reported to lower body temperature. Therefore, the findings that antidepressant drugs decrease hypothalamic temperature may be important in understanding their therapeutic mechanism. In light of the effects of antidepressant drugs on circadian variation of hypothalamic temperature, a second area of research has been to determine the chronic effects of clorgyline, an MAOI which a) chronically decreases hypothalamic temperature in hamsters and b) delays the circadian pacemaker, on brain monoamines in discrete brain nuclei reported to be involved in circadian regulation of behavior and thermoregulation. These studies indicate that chronic clorgyline treatment elevates serotonin (5HT) levels in terminal regions of the hypothalamus (suprachiasmatic nucleus, paraventricular nucleus, medial preoptic area) and thalamus (lateral geniculate nucleus), and in cell bodies of the dorsal and median raphe. It also elevates dopamine levels in the ventral tegmental area, the caudate nucleus and the nucleus accumbens. Furthermore, in all regions except the dorsal raphe nucleus and the suprachiasmatic nucleus, clorgyline treatment eliminated the circadian rhythm of 5HT that is normally present.